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Biomedical subjects

D W Gallager

Publications and source records attributed to D W Gallager.

At least 55 records · Page 3Linked to original sources
PubMed1986

Tolerance to anti-pentylenetetrazol effects following chronic diazepam.

Continuous release of diazepam from subcutaneously implanted silastic capsules provided significant protection against pentylenetetrazol seizures in rats for up to 3 weeks. However, the degree of protection seen after 3 weeks of exposure to diazepam was significantly less than after 1 h. These data suggest that continuous exposure to constant low levels of diazepam results in the development of partial tolerance which is not sufficient to eliminate significant anticonvulsant effects.

Animals↗
PubMed1985

Continuous release of diazepam: electrophysiological, biochemical and behavioral consequences.

Neuronal GABAergic sensitivity was assessed using electrophysiological, biochemical and behavioral techniques following the continuous release and maintenance of relatively constant brain levels of diazepam for greater than or equal to 21 days. Our studies indicate that long-term exposure to diazepam results in: (1) a decrease in iontophoretic sensitivity to GABA in the dorsal raphe nucleus, (2) an increase in the affinity of the GABA recognition site in brain tissue and (3) an increase in susceptibility to bicuculline-induced seizures in the intact animal. Since the decrease in GABAergic responsiveness was observed in the presence of measurable levels of diazepam, it was concluded that this subsensitivity phenomenon is associated with tolerance and not with withdrawal effects of the benzodiazepines.

Animals↗
PubMed1985

Electrophysiological and receptor studies in rat brain: effects of clorgyline.

Acute high doses of clorgyline produce a rapid inhibition of monoamine oxidase type A (MAO A) in the rat brain, together with an increase in norepinephrine and a decrease in the firing rate of locus coeruleus (LC) neurones: this decrease is reversed by piperoxane, an alpha 2 antagonist. In control animals, piperoxane increases LC neuronal firing showing that these noradrenergic neurones are under alpha 2-adrenoceptor-mediated tonic inhibition. Chronic administration of clorgyline, like acute doses of this MAO A inhibitor, significantly decreases cell firing in the LC and the effect is partially reversed by piperoxane. Chronic clorgyline treatment also produces significant decreases in [3H]clonidine and [3H]dihydroalprenolol binding in cerebral cortex, receptor changes which are slightly greater in animals showing greater inhibition of LC neuronal firing: such receptor changes do not occur following a single exposure to clorgyline. Electrophysiological studies in hippocampal pyramidal cells show that the chronic clorgyline treatment does not significantly induced subsensitivity to NE in these adrenoreceptive cells.

Animals↗
PubMed1985

Spontaneous and RO 15-1788-induced reversal of subsensitivity to GABA following chronic benzodiazepines.

Chronic daily injections of diazepam (5 mg/kg i.p.) for 21-30 days have previously been shown to cause a selective subsensitivity to microiontophoretically applied GABA in serotonergic dorsal raphe neurons in the rat. Following termination of chronic benzodiazepine treatment, GABAergic sensitivity remained depressed for up to 96 h even though pharmacologically active concentrations of diazepam and its active metabolites could no longer be detected in brain tissue. In contrast, a single injection of the specific benzodiazepine antagonist, RO 15-1788, given 22 h prior to electrophysiological recording, restored GABAergic sensitivity to the control range. Sensitivity of dorsal raphe neurons to serotonin was not altered by either chronic treatment with or withdrawal from diazepam. These results indicate that (1) RO 15-1788 can accelerate the time course of withdrawal and (2) administration of this benzodiazepine antagonist can induce a persistent change in GABAergic responsiveness.

Animals↗
PubMed1985

Spinalization unmasks clonidine's alpha 1-adrenergic mediated excitation of the flexor reflex in rats.

Clonidine exerts alpha 2-adrenergic mediated depressant effects on most behaviors measured in a normal animal. However, in the spinal-transected (spinalized) animal, clonidine apparently facilitates the flexor reflex through a stimulation of spinal alpha 1-adrenoceptors. The purpose of the present study was to determine if spinalization per se causes the shift in clonidine's profile from an alpha 2- to an alpha 1-adrenergic agonist. The hindlimb flexor reflex was elicited by electrical pulses delivered through electrodes implanted subcutaneously in the hindpaw and was measured with a force transducer and polygraph. In contrast to an alpha 2-adrenergic mediated inhibition of the flexor reflex in intact rats, clonidine produced an alpha 1-adrenergic mediated increase in flexor reflex amplitude in spinalized rats. Because decerebration did not alter the depression due to clonidine, and intraventricular (but not intrathecal) administration of oxymetazoline mimicked the effect of clonidine, the depressant effects of alpha 2-adrenergic agonists are mediated through alpha 2-adrenergic receptors localized in the brainstem. Alternate methods for inducing a functional spinal transection (spinal block with intrathecal procaine; spinal ligation) indicated that the shift in clonidine's effect from inhibition of the flexor reflex to excitation occurred immediately following spinalization. Spinal ligation did not produce alpha 1-adrenergic supersensitivity at 15 min or 2 hr after transection, as measured by alterations in [3H]prazosin receptor binding or behavioral responses to clonidine. Thus, the shift in clonidine's effects from alpha 2-adrenergic mediated inhibition of the flexor reflex in intact rats to alpha 1-adrenergic mediated excitation in spinalized rats results because spinal transection unmasks clonidine's alpha 1-adrenergic stimulatory effect. Other conditions under which clonidine exerts alpha 1-adrenoceptor mediated excitatory effects on behavior are discussed.

Adrenergic alpha-Agonists↗
PubMed1984

Histamine-induced depression of serotoninergic dorsal raphe neurons: antagonism by cimetidine, a reevaluation.

Microiontophoretic application of the histamine H2-receptor antagonist cimetidine selectively attenuated the histamine-induced, but not the gamma-aminobutyric acid (GABA)-induced, depression of serotoninergic cells recorded in the dorsal raphe nucleus of the rat. These data support the view that an H2-receptor mediates the effects of histamine on these serotoninergic neurons. We also now ascribe a previous report of GABA-like properties of cimetidine and metiamide to an impurity in the lots of these compounds used originally.

Animals↗
PubMed1983

Alpha 1-adrenoceptor denervation supersensitivity in brain: physiological and receptor binding studies.

Electrophysiological and radioligand binding methods were used to characterize noradrenergic denervation supersensitivity at alpha 1-adrenoceptors in rat thalamus. Denervation was accomplished either by intraventricular or intracerebral injection of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). In the physiological studies, the sensitivity of single lateral geniculate neurons to norepinephrine, carbachol, and serotonin was compared in sham and lesioned animals various times after 6-OHDA. Conducted in parallel were radioligand binding studies in which the density and affinity of thalamic alpha 1-adrenoceptors were measured with the specific antagonist [3H]prazosin. The results indicate that denervation produces a selective increase in the sensitivity of geniculate neurons to alpha 1-adrenergic stimulation and a concomitant increase in alpha 1-adrenoceptor density and agonist affinity.

Animals↗
PubMed1983

Functional supersensitivity of CNS alpha 1-adrenoceptors following chronic antidepressant treatment.

Chronic but not acute administration (21 days) of desipramine (10 mg/kg), amitriptyline (10 mg/kg) or iprindole (5 mg/kg) enhanced the stimulatory effect of the alpha 1-adrenergic agonist phenylephrine on the acoustic startle reflex when phenylephrine was infused into the subarachnoid space of the spinal cord. Comparable supersensitivity to phenylephrine also occurred 1 week after selective depletion of norepinephrine in the spinal cord via intrathecal administration of 6-hydroxydopamine. Behavioral supersensitivity to phenylephrine was associated with an increase in the number of 3H-prazosin binding sites following denervation but not following chronic antidepressant treatments. The results indicate that chronic antidepressant treatments may enhance functional alpha 1-adrenergic transmission through mechanisms different than those following denervation.

Amitriptyline↗
PubMed1983

Interaction of histamine H2-receptor antagonists with GABA and benzodiazepine binding sites in the CNS.

The histamine H2-receptor antagonist cimetidine potently inhibited [3H]muscimol and enhanced [3H]flunitrazepam binding in membranes prepared from several brain regions in the rat, including the dorsal raphe nucleus. As further examined in cortical membranes, this effect on both GABA and benzodiazepine binding sites was specific for imidazole-derived H2-receptor antagonists (potency: cimetidine greater than metiamide greater than tiotidine) and not observed with either several H1-receptor antagonists or histamine. These data indicate a striking similarity between the actions of cimetidine (and other imidazole-derived H2-receptor antagonists) and GABA on binding parameters at the GABA receptor complex.

Animals↗
PubMed1983

Behavior and binding: correlations between alpha 1-adrenergic stimulation of acoustic startle and alpha 1-adrenoceptor occupancy and number in rat lumbar spinal cord.

The relationship between alterations in alpha 1-adrenoceptors and behavioral effects of alpha 1-adrenergic agonists were investigated in a localized region of the rat central nervous system. Direct infusion of the alpha 1-adrenergic agonists, D-amphetamine or phenylephrine. into the subarachnoid space of the lumbar cord (intrathecal administration) increased the amplitude of the acoustic startle reflex, The magnitude of this behavioral facilitation correlated highly with the degree of alpha 1-adrenoceptor occupation measured by [3H]prazosin binding in lumbar spinal tissue. Using an in vitro estimate of receptor occupation, maximal potentiation of startle occurred following approximately 30% occupation of the receptors, using either D-amphetamine or phenylephrine. Intrathecal administration of 6-OHDA produced a 95% decrease in spinal norepinephrine and markedly enhanced the behavioral response to intrathecal phenylephrine as well as the number of alpha 1-adrenoceptors. The correlation between the time course of the behavioral and binding changes was 0.99. No change in receptor affinity (KD) or receptor occupation by phenylephrine was found after 6-OHDA. The data indicate that receptor binding parameters do have predictive value for behavior, especially if localized regions of the nervous system, critical to the behavior, are analyzed.

Acoustic Stimulation↗
PubMed1983

Chronic antidepressant treatment enhances agonist affinity of brain alpha 1-adrenoceptors.

Binding of [3H]prazosin, a selective alpha 1-adrenoceptor antagonist, to thalamic membranes was studied following chronic treatment of rats with tricyclic antidepressants. Rosenthal analysis showed no change in the number or affinity of antagonist binding sites; however, the ability of the alpha 1-agonist phenylephrine to compete for these sites was significantly enhanced after chronic tricyclic treatment. This result is consistent with previous studies showing physiological alpha 1-supersensitivity in thalamus after chronic antidepressant administration.

Amitriptyline↗
PubMed1983

Development changes in pharmacological responsivity of the acoustic startle reflex: effects of picrotoxin.

Using the acoustic startle reflex as the behavioral measure, qualitatively different responses to the GABA antagonist picrotoxin were obtained in developing rats before and after 21 days postnatal (PN) age. Dose-dependent increases in acoustic startle were seen following picrotoxin in PN day 15-16 rat pups. In contrast, dose-dependent decreases in startle following picrotoxin were observed in adult rats. The switch from excitation to inhibition of startle was found to occur abruptly on PN day 21. Excitatory responses to picrotoxin were also found in adult rats following localized infusions of picrotoxin into lumbar spinal cord regions, but not into the forebrain. These results give evidence that picrotoxin-sensitive sites that modulate increases in startle reflex behavior mature first and are analogous to sites in the adult spinal cord, whereas picrotoxin-sensitive sites that modulate decreases in startle reflex behavior mature later (greater than or equal to PN day 21) and are localized in more rostral brain areas.

Acoustic Stimulation↗
PubMed1983

Consequences of benzodiazepine receptor occupancy.

The pharmacological consequences of the occupancy of benzodiazepine receptors have been a recent area of active research. There is good agreement between the electrophysiological effects of benzodiazepines and their binding to benzodiazepine receptors when both are studied in vitro under identical conditions. Compounds of different structure from the benzodiazepines can occupy the receptor in a way, which produces little overt effect (imidazodiazepines) or actually causes actions opposite to the benzodiazepines (beta-carbolines, inverse agonists). Several biochemical tests (GABA-shift, photo-shift) for distinguishing these different behavioral properties are described. A model is described for the interactions at membranes of agonists, antagonists and inverse agonists with benzodiazepine receptors in the GABA receptor complex.

Animals↗
PubMed1982

Prenatal exposure to electroconvulsive seizures and phenytoin: development of benzodiazepine binding sites, reflex behaviors and seizure thresholds in exposed offspring.

Electroconvulsive seizures administered during the period of fetal benzodiazepine (BZ) binding site proliferation (days 16, 18 and 20 in gestation) significantly decreased the density of cerebral cortical benzodiazepine binding sites in exposed pups up to 21 days postnatal age. Significant decreases in seizure threshold were also found in exposed offspring. However, decreases in BZ sites were not accompanied by significant alterations in RO5-4864-displaceable benzodiazepine binding as seen after in utero exposure to phenytoin (DPH). Neither prenatal treatment affected the ability of GABA to enhance BZ binding in vitro. Prenatal exposure to electroshock delayed the onset of acoustic startle and eye-opening during postnatal development; similar effects were not seen following in utero exposure to DPH. These data suggest that prenatal exposure to seizures and DPH decrease postnatal BZ site proliferation by different mechanisms.

Animals↗